5-HT1A RECEPTOR AGONIST PROPERTIES OF THE ANTIPSYCHOTIC, NEMONAPRIDE - COMPARISON WITH BROMERGURIDE AND CLOZAPINE

5-HT1A receptor agonists are thought to enhance the antipsychotic-like effects of dopamine D-2 receptor antagonists while reducing their pot ential to produce extrapyramidal side effects. Thus, 5-HT1A receptor a gonist properties of mixed 5-HT1A receptor agonists/D-2 receptor antag onists might be of clinical importance. The antipsychotics, clozapine and nemonapride, and the putative antipsychotic, bromerguride, have in termediate to high affinity for 5-HT1A receptors. The present study ex amined the 5-HT1A receptor agonist activity of nemonapride and bromerg uride, in comparison with clozapine, which has partial 5-HT1A receptor agonist properties in vitro. Here, 5-HT1A receptor activation was exa mined in vitro, by measuring forskolin-stimulated cAMP accumulation in HeLa cells expressing human 5-HT1A receptors, and in vivo, by using m icrodialysis to measure the extracellular concentration of hippocampal 5-hydroxytryptamine (5-HT) in rats. Nemonapride markedly decreased bo th forskolin-stimulated cAMP accumulation and the extracellular concen tration of 5-HT; both effects were antagonized by the 5-HT1A receptor antagonist, ethoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohe xanecarboxamide (WAY100635). In contrast, clozapine only partially dec reased forskolin-stimulated cAMP accumulation and extracellular 5-HT, and only its effects on cAMP accumulation were attenuated by WAY100635 . Bromerguride decreased neither forskolin-stimulated cAMP accumulatio n nor extracellular 5-HT; instead, it antagonized the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tet ralin (8-OH-DPAT). The selective D-2 receptor antagonist, raclopride, affected neither forskolin-stimulated cAMP in vitro nor extracellular 5-HT in vivo. Thus, in contrast with clozapine and bromerguride, only the novel antipsychotic, nemonapride, exhibited marked 5-HT1A receptor agonist properties both in vitro and in vivo; conceivably, these prop erties may play a role in its preclinical and clinical effects. (C) 19 97 Elsevier Science B.V.